Active targeting towards bone cancer and metastases by pamidronate-bridged dinuclear platinum(II) complexes

Bisphosphonates (BPs) are clinically established bone-seeking agents that strongly bind to hydroxyapatite and selectively accumulate at sites of active bone remodeling. Among nitrogen-containing BPs, pamidronate (PAM) is widely used for the management of cancer-related bone complications and has also been associated with antiproliferative and pro-apoptotic effects in several tumor models. These properties make PAM an attractive ligand for the development of potential bone-targeted anticancer agents, particularly in the context of primary bone tumors and bone metastases, which are difficult to treat and are frequently associated with severe pain and skeletal complications. Platinum-based chemotherapeutics are effective anticancer agents, but their clinical use is often limited by poor tissue selectivity, systemic toxicity, and drug resistance. In this work, we report the synthesis and full characterization of two novel dinuclear platinum(II)-PAM complexes in which PAM acts as a bridging ligand between two platinum centers containing either an oxaliplatin-derived [Pt(1R,2R-diaminocyclohexane)]²⁺ unit or a kiteplatin-derived [Pt(cis-1,4-diaminocyclohexane)]²⁺ unit. The new compounds were characterized by multinuclear NMR spectroscopy and ESI-MS, and their chemical stability was investigated under physiological and mildly acidic conditions. Their reactivity toward DNA models and their in vitro antiproliferative activity against breast adenocarcinoma and osteosarcoma cells were also evaluated. Overall, these results highlight the influence of both the bisphosphonate scaffold and the diamine carrier ligand on the chemical and biological properties of dinuclear platinum(II) complexes, supporting their further investigation as potential agents for the treatment of bone malignancies.